The use of stem cells and stem cell derivatives has gained increased interest in medical research, particularly in the area of providing reagents for treating tissue damage that result from genetic defects, injuries, and/or disease processes. Ideally, cells that are capable of differentiating into the affected cell types could be transplanted into a subject in need thereof, where they would interact with the organ microenvironment and supply the necessary cell types to repair the injury.
Stem cells can be harvested from a number of organs, including the bone marrow, adipose tissue, skeletal muscle, and other organs. Considerable effort has been expended to isolate adult stem cells from a number of different tissues for use in regenerative medicine. For example, U.S. Pat. No. 5,750,397 to Tsukamoto et al. discloses the isolation and growth of human hematopoietic stem cells that are reported to be capable of differentiating into lymphoid, erythroid, and myelomonocytic lineages. U.S. Pat. No. 5,736,396 to Bruder et al. discloses methods for lineage-directed differentiation of isolated human mesenchymal stem cells under the influence of appropriate growth and/or differentiation factors. The derived cells can then be introduced into a host for mesenchymal tissue regeneration or repair.
Traditionally, adherent primitive cells (also termed “mesenchymal stem cells”) are isolated via adhesion to plastic for 24-72 hours. However, it is well known that the population of cells isolated via adhesion is considerably heterogeneous in terms of phenotype, antigen expression, morphology, biological activities, and differentiation potential. Bone marrow (BM)-derived mesenchymal stem cells (MSCs), for example, can be induced to differentiate into osteogenic, chondrogenic, adipogenic, myogenic, neural, and other nonhematopoietic lineages.
Ischemic heart disease is the single most prevalent cause of death and morbidity in the USA (Heart Disease and Stroke Statistics, 2006). Despite pharmacotherapy, the infarcted left ventricle (LV) undergoes progressive remodeling leading to permanent impairment of cardiac function and development of congestive heart failure (Pfeffer et al., 1979; Pfeffer et al. 1990; McMurray & Pfeffer, 2005). Since no intervention is currently available for restoring the lost myocardial tissue, the treatment of post-myocardial infarction (MI) heart failure remains palliative and the prognosis for patients with large MI remains poor (Braunwald & Bristow, 2000; McMurray & Pfeffer, 2005). Although recent evidence indicates that therapy with BM-derived cells can improve LV function, ameliorate remodeling, and improve perfusion, the benefits have varied tremendously from one study to another and the underlying mechanisms remain highly controversial (Vassilopoulos et al. 2003; Wang et al. 2003; Chien, 2004; Balsam et al. 2004; Murry et al. 2004; Laflamme & Murry, 2005).
This inconsistency has significant consequences on the usefulness of these mixed cell populations for in vivo therapeutic purposes. For example, while clinical trials of MSC therapy for infarct repair are already underway, a critical examination of studies in vitro and cardiac repair in vivo has revealed a profound lack of consistency in major findings, including MSC-induced angiogenesis, myogenesis, anti-apoptotic effects, and a combination thereof, often termed “paracrine effects”. The bases for this inconsistency of performance are currently unknown.
Thus, there continues to be a need for new approaches to generate populations of transplantable cells suitable for a variety of applications, including but not limited to treating injury and/or disease of various organs and/or tissues.